A Computational Approach to Study the Structural Ensembles of Genes

Genomes fold into architectures that are characteristic of both cell phase and cell type. The spatial organization of genes orchestrates interactions among genetic regulatory elements that ultimately contribute to gene regulation in organisms and tissues. Understanding the principles underlying genomic architecture and its effect on transcriptional regulation is a major undertaking with far-reaching implications in basic science, medicine, and technology. As experimental information about the spatial conformation of genes becomes available, accurate theoretical models are increasingly needed to interpret this data. Unfortunately, theoretical models for genes are being outpaced by developments in experimental approaches. This is partially because genes are molecular systems that are simultaneously too big to be studied with conventional molecular dynamics simulations and too heterogeneous to be tackled with polymer physics-based approaches. This goal of this award is to fill this gap by developing a new theoretical approach to studying genes using the framework of Associative Memory Hamiltonians. The proposed theoretical model would enable molecular dynamics simulations of tens of thousands of DNA base pairs together with the proteins decorating the fiber, representing specific genes or gene clusters. The model allows integration of a vast amount of information that is already known for the smaller molecular scale to study the mostly unknown conformations of genes, much larger systems. The objectives of the project are: (i) to faithfully model the mechanics of chromatin at gene scale, given information about the positioning of proteins that bind along the DNA polymer, (ii) to study how genomic conformational ensembles are affected by supercoiling, nucleosome occupancy, specific histone variants, and the presence of other proteins such as polymerases or transcription factors, (iii) to elucidate how essential physical contacts related to the operation of the genome, e.g. enhancer-promoter interactions, are orchestrated by the three-dimensional architecture of genes. In addition, the PI participates to several existing outreach programs aimed to fostering participation of underrepresented groups to research in biophysics. Undergraduate students recruited through these programs will participate in the research proposed with projects involving developing scientific software. The software engineering skills acquired through these projects will increase students’ competitiveness in the pursuit of graduate education and employment. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.